To determine the role of surfactant protein-A(SP-A) in antiviral host defense, mice lacking SP-A (SP-A -/-) were produced by targeted gene inactivation. SP-A -/-and control mice (SP-A +/+ ) were infected with respiratory syncytial virus (RSV) by intratracheal instillation. Pulmonary infiltration after infection was more severe in SP-A -/-than in SP-A +/+ mice and was associated with increased RSV plaque-forming units in lung homogenates. Pulmonary infiltration with polymorphonuclear leukocytes was greater in the SP-A -/-mice. Levels of proinflammatory cytokines tumor necrosis factor-α and interleukin-6 were enhanced in lungs of SP-A -/-mice. After RSV infection, superoxide and hydrogen peroxide generation was deficient in macrophages from SP-A -/-mice, demonstrating a critical role of SP-A in oxidant production associated with RSV infection. Coadministration of RSV with exogenous SP-A reduced viral titers and inflammatory cells in the lung of SP-A -/-mice. These findings demonstrate that SP-A plays an important host defense role against RSV in vivo.

To determine the role of surfactant protein-A (SP-A) in host defense, the murine SP-A locus was targeted by homologous recombination to produce mice lacking SP-A. SP-A-/- and wild-type mice were infected with mucoid Pseudomonas aeruginosa by intratracheal instillation. Pulmonary bacterial loads were greater in SP-A-/- than in wild-type mice, with increased numbers of mucoid P. aeruginosa in lung homogenates at 6 and 24 h after infection. Pulmonary infiltration with polymorphonuclear leukocytes (PMN) was similar in both groups; however, an earlier influx of PMN into the lung occurred in the SP-A-/- mice. The number of bacteria phagocytosed by alveolar macrophages was decreased in the SP-A-/- mice at 1 h after infection. Superoxide-radical generation by PMN was similar for the SP-A-/- and wild-type mice, but nitrite levels were increased in SP-A-/- mice. Concentrations of tumor necrosis factor-alpha, interleukin-6, and macrophage inflammatory protein-2 (proinflammatory cytokines) were greater in bronchoalveolar lavage fluid at 2 h after infection in SP-A-/- mice. SP-A plays an important role in the pathogenesis of mucoid P. aeruginosa infection in the lung in vivo by enhancing macrophage phagocytosis and clearance of bacteria, and by modifying the inflammatory response.

Inflammation of the human airways in diseases such as chronic bronchitis, cystic fibrosis with Pseudomonas endobronchial infection, and possibly asthma during late-phase reactions involves a local influx of neutrophils (PMN) that may participate in airway epithelial injury. PMN-mediated cellular injury is most efficient under conditions of PMN-target cell adhesion. PMN express adhesive glycoproteins of the CD11/CD18 family that are counter-receptors for intercellular adhesion molecule-1 (ICAM-1), found on various cell types. We proposed that adherence by PMN to human airway epithelial cells via ICAM-1 might be an important mechanism in inflammatory airway diseases. We found that although PMN adhere poorly (less than 5%) to monolayers of human tracheal epithelial cells (TEC) in primary culture, they adhere readily (45 to 50%) to an SV40-immortalized line of human TEC, designated 9HTEo-. We also found 6-fold greater surface expression of ICAM-1 on 9HTEo- compared with primary TEC. Blocking surface ICAM-1 on 9HTEo- cells with specific monoclonal antibody inhibited PMN adherence by about 50%. Thus, ICAM-1 plays a major role in this adherence, although it is possible that other epithelial ligands contribute also. Antibodies to CD11a, CD11b, and CD18 on PMN also inhibited PMN-epithelial adherence. Treatment of primary TEC monolayers with the proinflammatory cytokines interleukin-1 (IL-1) or tumor necrosis factor-alpha (TNF-alpha) caused a 3- to 4-fold increase in both cell surface ICAM-1 expression and support of PMN adhesion.(ABSTRACT TRUNCATED AT 250 WORDS)